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(e) Dilman , A. D.; Levin , V. V. Mendeleev Commun. 2015, 25, 239– ...... (a) Kosobokov , M. D.; Levin , V. V.; Struchkova , M. I.; Dilman , A. D. O...
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Silicon Reagent with Functionalized Tetrafluoroethylene Fragments: Preparation and Coupling with Aldehydes Oleg V. Fedorov, Marina I. Struchkova, and Alexander D. Dilman* N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russia S Supporting Information *

ABSTRACT: A new fluorinated silicon reagent bearing a functionalized tetrafluoroethylene fragment was prepared from two CF2 building blocks: ethyl bromodifluoroacetate and (bromodifluoromethyl)trimethylsilane. The key C− C bond-forming step involves a difluorocarbene addition/cyclopropane rearrangement sequence. The silicon reagent was coupled with aldehydes and reactive azomethines in the presence of potassium fluoride. Ethyl bromodifluoroactetate was first converted into silyl ketene acetal 2 by treatment with zinc and chlorosilane in acetonitrile (Scheme 2). This reaction proceeds with the yield

F

luorinated silanes constitute an important class of reagents for the synthesis of valuable organofluorine compounds.1,2 While these reagents are typically air-stable and themselves are unreactive toward electrophiles, they display nucleophilic reactivity when activated by a suitable Lewis base. As a consequence, fluorinated silanes have found widespread applications as a source of nucleophilic fluorinated fragment in reactions with CO, CN, and CC bonds2 as well as in transition-metal catalyzed cross-couplings.3 The Ruppert-Prakash reagent (Me3SiCF3) and its homologues (Me3SiCnF2n+2) are the most frequently employed silanes and are quite well-studied.2a,b At the same time, functionalized silanes containing a CF2CF2 unit are rare, which may be associated with limited approaches for their synthesis.4 Indeed, a general method for the preparation of such silanes relies on dibromotetrafluoroethane as a starting compound and involves substitution of one bromine and reductive silylation of the other4,5 (Scheme 1). Given the

Scheme 2. Synthesis of Reagent 1a

around 40%. Furthermore, compound 2 is prone to transformation into thermodynamically more stable C-silyl tautomer.12 The crude material was dissolved in dichloromethane and reacted with (bromodifluoromethyl)trimethylsilane (Me3SiCF2Br) and hexamethylphosphoramide (HMPA), affording, after distillation, product 1a in 80% yield based on Me3SiCF2Br. Concerning the mechanism, the combination of Me3SiCF2Br and HMPA generates difluorocarbene,13 which easily adds to electron-rich double bond of 2.10,14,15 Cyclopropane 3 is unstable and cannot be detected by monitoring of the reaction by 19F NMR spectroscopy. As it is formed, it rapidly rearranges into product 1a, similar to cyclopropanes derived from nonfluorinated ketene acetals.10a The mechanism of the rearrangement of 3 into 1a is not clear at present, but dissociative C−C bond-breaking owing to strongly donating oxygen atoms seems likely. As a fluorinated silicon reagent, silane 1a was first tested in fluoride-mediated reaction with benzaldehyde 4a (Scheme 3). Under various conditions, complex mixtures containing small amounts of expected product 5a were formed. Iminium ions are

Scheme 1. Functionalized Silicon Reagents

growing interest toward compounds with tetrafluoroethylene fragments,6−8 the elaboration of fluorinated silanes bearing a modifiable functional group is important. Herein, we describe new silicon reagents, ester and amido substituted silanes 1, which can be readily obtained from ethyl bromodifluoroactetate and a source of difluorocarbene. This process constitutes a rare example of C−C bond forming process between two different CF2 fragments.9 Our concept is based on the difluorohomologation approach recently reported by our group.10,11 © 2016 American Chemical Society

Received: July 21, 2016 Published: September 14, 2016 9455

DOI: 10.1021/acs.joc.6b01739 J. Org. Chem. 2016, 81, 9455−9460

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The Journal of Organic Chemistry Scheme 3. Reactions of Silane 1a

Table 1. Reactions of Aldehydes with Silane 1b

also good substrates for coupling with fluorinated nucleophiles.16 When iminium salt 6 was coupled with silane 1a, addition product 7a was cleanly formed, as evidenced by 19F NMR, but we could not isolate it by silica gel chromatography. These facts may be associated with the high electrophilic activity of the ester carbonyl group, which causes cyclization of 5a (or its alkoxide form) or decomposition of 7a on silica gel. Correspondingly, when crude material containing 7a was treated with pyrrolidine, amide 7b was formed, and it was easily isolated after conventional chromatography in 46% yield. The increased stability of the amide 7b compared to ester 7a prompted us to modify the silane 1a by converting the ester into an amide group. It should be pointed out that modifications of side chains of fluorinated silanes under nucleophilic conditions is problematic owing to facile cleavage of the C−Si bond. Indeed, interaction of silane 1a with pyrrolidine provided a mixture of protodesilylated products (Scheme 4). Rewardingly, reaction of 1a with N-silylpyrrolidine Scheme 4. Synthesis of Silane 1b

proceeded cleanly in pentane, furnishing silane 1b in 99% isolated yield. Attempted preparation of silane 1b directly from N-(bromodifluoroacetyl)pyrrolidine was unsuccessful presumably because of difficulties with generation of intermediate silyl ketene aminal. A series of aldehydes 4 were coupled with silane 1b (Table 1). Under the optimized conditions, 2 equiv of potassium fluoride in dimethylformamide (DMF) was used with reaction time of 1 h followed by desilylation.17 Aromatic and heteroaromatic aldehydes gave good yields of products. Cinnamaldehyde and enolizable substrates also worked well (entries 12−14). Only p-methoxybenzaldehyde exhibited decreased reactivity and afforded addition product in moderate yield (entry 6). Acetophenone turned out to be unreactive, and selfcondensation of the silicon reagent proceeded faster than that of the carbonyl addition reaction. Thus, when silane 1b was subjected to potassium fluoride without carbonyl substrate, compound 9 was formed in 63% yield (determined by 19F NMR) along with other byproducts (Scheme 5). From the complex mixture, compound 9 was isolated in individual form

a

Isolated yield.

Scheme 5. Self-Condensation of Silane 1b

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DOI: 10.1021/acs.joc.6b01739 J. Org. Chem. 2016, 81, 9455−9460

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The Journal of Organic Chemistry

(bromodifluoromethyl)trimethylsilane). Colorless oil. 1H NMR (300 MHz, CDCl3) δ: 4.38 (q, 2H, J = 7.1 Hz), 1.36 (t, 3H, J = 7.1), 0.28 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3) δ: 161.0 (t, J = 31.3 Hz), 122.4 (tt, J = 271.7, 44.1 Hz), 112.0 (tt, J = 255.2, 32.6 Hz), 63.5, 14.0, −4.2. 19 F NMR (282 MHz, CDCl3) δ: −116.9 (s, 2F), −127.8 (s, 2F). HRMS (ESI): calcd for C8H14F4O2NaSi (M + Na) 269.0591; found 269.0580. 1-[2,2,3,3-Tetrafluoro-3-(trimethylsilyl)propanoyl]pyrrolidine (1b). N-(trimethylsilyl)pyrrolidine (2.91 g., 20.3 mmol) was added dropwise to a solution of silane 1a (5 g, 20.3 mmol) in pentane (0.5 mL) at 0 °C. The cooling bath was removed, and the mixture was stirred overnight at room temperature. All volatiles were evaporated in vacuum, and the residue was purified by flash chromatography on silica gel (Rf 0.36, hexane/EtOAc, 6/1,). Yield: 5.48 g, 99%. Colorless oil. 1H NMR (300 MHz, CDCl3) δ: 3.71 (t, 2H, J = 6.6 Hz), 3.58 (t, 2H, J = 6.9 Hz), 2.01−1.80 (m, 4H), 0.29 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3) δ: 159.3 (t, J = 27.5 Hz), 123.3 (tt, J = 271.9, 39.0 Hz), 113.5 (tt, J = 258.7, 29.8 Hz), 47.9, 46.9 (m), 26.6, 23.3, −3.8. 19F NMR (282 MHz, CDCl3) δ: −115.1 (s, 2F), −128.4 (s, 2F). HRMS (ESI): calcd for C10H18F4NOSi (M + H) 272.1088; found 272.1094. Reactions of Aldehydes with Silane 1b (General Procedure). A solution of aldehyde 4 (0.5 mmol) and silane 1b (203 mg, 0.75 mmol) in DMF (0.25 mL) was cooled to −10 °C, and potassium fluoride (58 mg, 1 mmol) was added. The mixture was allowed to warm to room temperature over 15 min and stirred for an additional 45 min. The mixture was treated with Bu4NF·3H2O (316 mg, 1 mmol) and stirred for 10 min. Then, water (3 mL) was added, and the aqueous phase was extracted with ethyl acetate (3 × 4 mL). The combined organic layers were filtered through Na 2SO4 and concentrated under vacuum, and the residue was purified by column chromatography. 2,2,3,3-Tetrafluoro-4-hydroxy-4-phenyl-1-(pyrrolidin-1-yl)butan1-one (8a). Yield 116 mg (76%). Colorless crystals. Mp 76−77 °C. Rf 0.36 (hexane/EtOAc, 2/1). 1H NMR (300 MHz, CDCl3) δ: 7.54− 7.43 (m, 2H), 7.43−7.31 (m, 3H), 5.27−5.15 (m, 1H), 4.58 (d, 1H, J = 3.8 Hz), 3.88−3.68 (m, 2H), 3.63 (t, 2H, J = 6.9 Hz), 2.11−1.79 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3) δ: 160.4 (t, J = 27.1 Hz), 135.0, 129.0, 128.32, 128.26, 115.8 (dddd, J = 262.8, 258.2, 29.8, 24.1 Hz), 111.9 (dddd, J = 269.6, 262.8 35.6, 28.7 Hz), 72.0 (dd, J = 28.7, 21.9 Hz), 48.6, 47.5 (t, J = 6.0 Hz), 26.6, 23.2. 19F NMR (282 MHz, CDCl3) δ: −114.8 (ddd, 1F, J = 278.2, 13.1, 5.6 Hz), −117.0 (dd, 1F, J = 278.2, 11.0 Hz), −116.3 (dd, 1F, J = 273.0, 11.0 Hz), −130.8 (dddd, 1F, J = 273.2., 21.6, 13.1, 6.7 Hz). HRMS (ESI): calcd for C14H15F4NNaO2 (M + Na) 328.0931; found 328.0934. Methyl 4-(2,2,3,3-Tetrafluoro-1-hydroxy-4-oxo-4-(pyrrolidin-1yl)butyl)benzoate (8b). Yield 154 mg (85%). Colorless crystals. Mp 129−130 °C. Rf 0.29 (hexane/EtOAc, 1/1). 1H NMR (300 MHz, CDCl3) δ: 7.99 (d, 2H, J = 8.1 Hz), 7.52 (d, 2H, J = 8.1 Hz), 5.26 (d, 1H, JH−F = 20.7 Hz), 5.01 (s, 1H), 3.86 (s, 3H), 3.74−3.60 (m, 2H), 3.55 (t, 2H, J = 6.8 Hz), 2.04−1.71 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3) δ: 166.9 (s), 160.2 (t, J = 27.0 Hz), 140.0, 130.7, 129.4, 128.3, 115.5 (m), 111.8 (m), 71.7 (dd, J = 28.5, 22.1 Hz), 52.2, 48.6, 47.4 (t, J = 6.0 Hz), 26.5, 23.2. 19F NMR (300 MHz, CDCl3) δ: −114.8 (dd, 1F, J = 279.7, 10.6 Hz), −116.8 (dd, 1F, J = 279.7, 8.5 Hz), −117.5 (dd, 1F, J = 273.4, 10.6 Hz), −129.9 (dddd, 1F, J = 273.4, 20.7, 10.6, 4.2 Hz). HRMS (ESI): calcd for C16H18F4NO4 (M + H) 364.1166; found 364.1161. 4-(2,2,3,3-Tetrafluoro-1-hydroxy-4-oxo-4-(pyrrolidin-1-yl)butyl)benzonitrile (8c). Yield 134 mg (81%). Colorless crystals. Mp 107− 108 °C. Rf 0.30 (hexane/EtOAc, 1/1). 1H NMR (300 MHz, CDCl3) δ: 7.62 (d, 2H, J = 8.4 Hz), 7.57 (d, 2H, J = 8.4 Hz), 5.36−5.16 (m, 2H), 5.20 (s, 1H), 3.70 (t, 2H, J = 6.5 Hz), 3.55 (t, 2H, J = 6.9 Hz), 2.07−1.76 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3), δ: 160.0 (t, J = 27.0 Hz), 140.3, 131.9, 129.1, 118.6, 115.3 (dddd, J = 263.9, 259.3, 29.8, 24.1 Hz), 112.7, 111.5 (dddd, J = 269.6, 263.9, 34.4, 26.7 Hz), 71.3 (dd, J = 28.4, 22.1 Hz), 48.6, 47.4 (m), 26.5, 23.1. 19F NMR (282 MHz, CDCl3) δ: −114.6 (dd, 1F, J = 280.3, 10.6 Hz), −116.6 (dd, 1F, J = 280.3, 10.6 Hz), −117.2 (dd, 1F, J = 274.1, 10.6 Hz), −130.0 (dddd, 1F, J = 274.1, 21.5, 12.9, 6.8 Hz). HRMS (ESI): calcd for C15H15F4N2O2 (M + H) 331.1064; found 331.1058.

by preparative HPLC. Supposedly, the mechanism of selfcondensation involves fluoride-initiated α- or β-elimination of fluorosilane with the generation of trifluoroacrylamide, which reacts with another molecule of 1b.18 Besides aldehydes, iminium salt 6 and N-tosyl imine 10 were coupled with silane 1b, leading to products 7b and 11, respectively (Scheme 6). Scheme 6. Reactions of Azomethine Substrates

In summary, a novel functionalized fluorinated silicon reagent is described. The reagent contains a tetrafluoroethylene fragment which is assembled from two CF2 building blocks. While coupling of the silane with aldehydes and reactive azomethines proceeds smoothly, its propensity for selfcondensation under basic conditions renders problematic nucleophilic fluoroalkylation of less-reactive substrates.

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EXPERIMENTAL SECTION

General Methods. All reactions were performed under an argon atmosphere. Acetonitrile and HMPA were distilled from CaH2 and stored over MS 4A. Column chromatography was carried out, employing silica gel (230−400 mesh). Precoated silica gel plates F254 were used for thin-layer analytical chromatography visualizing with UV and/or acidic aq. KMnO4 solution. High-resolution mass spectra (HRMS) were measured using electrospray ionization (ESI) and timeof-flight (TOF) mass analyzer. The measurements were done in a positive ion mode (interface capillary voltage −4500 V) or in a negative ion mode (3200 V); mass range from m/z 50 to 3000. Me3SiCF2Br9a was prepared according to literature procedure. Ethyl 2,2,3,3-Tetrafluoro-3-(trimethylsilyl)propanoate (1a). Zinc dust (12.8 g, 200 mmol, 2 equiv) was placed in a Shlenk tube and heated to 100 °C under vacuum (5 Torr). After being cooled to room temperature, the reaction vessel was filled with argon. Then, MeCN (15 mL), Me3SiCl (763 mg, 7 mmol), and 1,2-dibromoethane (94 mg) were successively added, and the mixture was stirred for 30 min. The mixture was cooled to −10 °C, and a solution of ethyl bromodifluoroacetate (20.2 g, 100 mmol) in MeCN (15 mL) was added over 50 min using the syringe pump. After completion of the addition, the cooling bath was removed, and the mixture was allowed to warm to room temperature and stirred for 1 h. Then, the mixture was cooled to 0 °C; Me3SiCl (16.4 g, 150 mmol) was added dropwise, and the mixture was allowed to warm to room temperature over 45 min. Under argon atmosphere, the mixture was extracted with pentane (4 × 25 mL, pentane phase was decanted using a cannula). Combined pentane layers were placed in a 250 mL flask, and 75% of the pentane was evaporated under vacuum (40−50 Torr). The residue was diluted with dichloromethane (25 mL), and the mixture was cooled to 0 °C. Then, (bromodifluoromethyl)trimethylsilane (10 g, 50 mmol) and HMPA (11 g, 61 mmol) were successively added dropwise. The cooling bath was removed, and the mixture was stirred for 3 h at room temperature. The mixture was concentrated under vacuum (10−15 Torr); the residue was dissolved in pentane (70 mL), and water (15 mL) was added. The mixture was washed with pentane (3 × 70 mL); the combined pentane extracts were filtered through Na2SO4 and concentrated, and the residue was further purified by fractional distillation (55−53 °C/2.6 Torr). Yield: 9.82 g (80%, based on 9457

DOI: 10.1021/acs.joc.6b01739 J. Org. Chem. 2016, 81, 9455−9460

Note

The Journal of Organic Chemistry 2,2,3,3-Tetrafluoro-4-hydroxy-4-(4-nitrophenyl)-1-(pyrrolidin-1yl)butan-1-one (8d). Yield 128 mg (73%). Colorless crystals. Mp 132−133 °C. Rf 0.36 (hexane/EtOAc, 1/2). 1H NMR (300 MHz, acetone-d6) δ: 8.33−8.25 (m, 2H), 7.86−7.79 (m, 2H), 5.86 (d, 1H, J = 5.7 Hz), 5.69 (dt, 1H, JH−F = 19.0 Hz, J = 5.7 Hz), 3.80−3.70 (m, 2H), 3.55 (t, 2H, J = 6.9 Hz), 2.09−1.85 (m, 4H). 13C{1H} NMR (75 MHz, acetone-d6) δ: 159.2 (dd, J = 27.2, 26.6 Hz), 149.2, 144.5 (m), 130.4, 123.9, 116.9 (ddt, J = 261.8, 256.1, 27.2 Hz), 112.3 (tdd, J = 266.5, 32.0, 30.4 Hz), 71.7 (dd, J = 27.8, 22.1 Hz), 48.8, 47.6 (t, J = 6.3 Hz), 27.1 (t, J = 1.7), 23.7. 19F NMR (282 MHz, acetone-d6) δ: −115.6 (m, 2F), −118.7 (d, 1F, J = 270.9 Hz), −128.2 (dd, 1F, J = 270.9, 19.0 Hz). HRMS (ESI): calcd for C14H15F4N2O4 (M + H) 351.0962; found 351.0962. 2,2,3,3-Tetrafluoro-4-hydroxy-1-(pyrrolidin-1-yl)-4-(4(trifluoromethyl)phenyl)butan-1-one (8e). Yield 146 mg (78%). Colorless crystals. Mp 93−94 °C. Rf 0.35 (hexane/EtOAc, 1/1). 1H NMR (300 MHz, CDCl3) δ: 7.67−7.54 (m, 4H), 5.28 (d, 1H, JH−F = 21.1 Hz), 5.04 (d, 1H, J = 3.9 Hz), 3.79−3.69 (m, 2H), 3.61 (t, 2H, J = 6.9 Hz), 2.07−1.83 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3) δ: 160.1 (t, J = 27.0 Hz), 139.2, 131.1 (q, J = 32.5 Hz), 128.8, 125.1 (q, J = 3.7 Hz), 124.2 (q, J = 272.3 Hz), 115.5 (m), 112.0 (m), 71.5 (dd, J = 28.5, 22.1 Hz), 48.6, 47.4 (m), 26.5, 23.2. 19F NMR (282 MHz, CDCl3) δ: − 63.5 (s, 3F), −114.7 (dd, 1F, J = 280.1, 7.0 Hz), −117.0 (dd, 1F, J = 280.0, 11.2 Hz), −117.2 (dd, 1F, J = 273.6, 12.0 Hz), −130.5 (dddd, 1F, J = 273.6, 21.1, 12.7, 7.0 Hz). HRMS (ESI): calcd for C15H15F7NO2 (M + H) 374.0986; found 374.0981. 2,2,3,3-Tetrafluoro-4-hydroxy-4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (8f). Yield 84 mg (50%). Colorless crystals. Mp 97−98 °C. Rf 0.30 (hexane/EtOAc, 1/1). 1H NMR (300 MHz, CDCl3) δ: 7.39 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.16 (d, JH−F = 21.3 Hz, 1H), 4.45 (d, J = 4.0 Hz, 1H), 3.80 (s, 3H), 3.78−3.68 (m, 2H), 3.62 (t, J = 6.9 Hz, 2H), 2.08−1.80 (m, 4H). 13C NMR (75 MHz, CDCl3) δ: 160.3 (t, J = 26.9 Hz), 160.2, 129.5, 127.0, 115.9 (dddd, J = 261.6, 257.0, 29.8, 24.1 Hz), 113.7, 112.1 (dddd, J = 269.6, 263.9, 35.6, 29.8 Hz), 71.58 (dd, J = 29.0, 21.8 Hz), 55.4, 48.6, 47.5 (t, J = 5.7 Hz), 26.6, 23.2. 19F NMR (282 MHz, CDCl3) δ: −114.8 (dd, 1F, J = 278.3, 10.7 Hz), −117.0 (dd, 1F, J = 278.3, 10.8 Hz), −117.4 (dd, 1F, J = 272.0, 11.9 Hz), −131.0 (dddd, 1F, J = 272.0, 21.3, 10.7, 4.7 Hz). HRMS (ESI): calcd for C15H18F4NO3 (M + H) 336.1217; found 336.1215. 4-(4-Bromophenyl)-2,2,3,3-tetrafluoro-4-hydroxy-1-(pyrrolidin-1yl)butan-1-one (8g). Yield 142 mg (74%). Colorless crystals. Mp 119−120 °C. Rf 0.27 (hexane/EtOAc, 1/1). 1H NMR (300 MHz, CDCl3) δ: 7.51 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 8.4 Hz), 5.17 (d, 1H, JH−F = 21.1 Hz), 4.78 (s, 1H), 3.84−3.70 (m, 2H), 3.63 (t, 2H, J = 6.9 Hz), 2.10−1.83 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3) δ: 160.4 (t, J = 26.9 Hz), 134.0, 131.5, 130.0, 123.2, 115.6 (m), 111.8 (m), 71.5 (dd, J = 28.7, 22.1 Hz), 48.7, 47.5 (m), 26.6, 23.3. 19F NMR (282 MHz, CDCl3) δ: −114.7 (ddd, 1F, J = 279.7, 12.6, 5.3 Hz), −116.9 (dd, 1F, J = 279.3, 11.7 Hz), −117.2 (dd, 1F, J = 273.4, 12.6 Hz), −130.9 (dddd, 1F, J = 273.4, 21.1, 12.6, 5.3). HRMS (ESI): calcd for C14H14BrF4NNaO2 (M + Na) 406.0036, 408.0016; found 406.0029, 408.0007. 2,2,3,3-Tetrafluoro-4-(2-fluorophenyl)-4-hydroxy-1-(pyrrolidin-1yl)butan-1-one (8h). Yield 118 mg (73%). Colorless oil. Rf 0.26 (hexane/EtOAc, 2/1). 1H NMR (300 MHz, CDCl3) δ: 7.65 (t, 1H, J = 7.4 Hz), 7.41−7.29 (m, 1H), 7.19 (td, 1H, J = 7.5, 0.9 Hz), 7.11− 6.97 (m, 1H), 5.64 (d, 1H, JH−F = 21.6 Hz), 4.84 (s, 1H), 3.75 (s, 2H), 3.62 (t, 2H, J = 6.9 Hz), 2.06−1.83 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3) δ: 160.7 (d, J = 247.2 Hz), 160.2 (t, J = 25.8 Hz), 130.5 (d, J = 8.0 Hz), 129.7 (d, J = 2.0 Hz), 124.2 (d, J = 3.3 Hz), 122.5 (d, J = 13.1 Hz), 115.5 (m), 115.1 (d, J = 22.4 Hz), 111.9 (m), 65.1 (ddd, J = 29.8, 21.8, 4.0 Hz), 48.6, 47.4 (m), 26.5, 23.2. 19F NMR (282 MHz, CDCl3) δ: −115.0 (ddd, 1F, J = 279.0, 11.8, 6.8 Hz), −117.7 (dd, 1F, J = 279.0, 12.4 Hz), −118.5 (m, 1F), −118.6 (m, 1F), −131.3 (m, 1F). HRMS (ESI): calcd for C14H14F5NNaO2 (M + Na) 346.0837; found 346.0833. 2,2,3,3-Tetrafluoro-4-hydroxy-4-(pyridin-2-yl)-1-(pyrrolidin-1-yl)butan-1-one (8i). Yield 137 mg (89%). Colorless oil. Rf 0.25 (hexane/ EtOAc, 1/1). 1H NMR (300 MHz, CDCl3) δ: 8.56 (d, 1H, J = 4.7

Hz), 7.71 (td, 1H, J = 7.8, 1.6 Hz), 7.46 (d, 1H, J = 7.8 Hz), 7.34−7.24 (m, 1H), 5.40 (s, 1H), 5.43−5.31 (m, 2H), 3.70 (t, 1H, J = 6.7 Hz), 3.56 (t, 1H, J = 6.9 Hz), 2.00−1.77 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ: 159.0 (t, J = 26.8 Hz), 152.6, 148.3, 136.8, 124.0, 123.3 (d, J = 3.2 Hz), 115.7 (m), 111.3 (m), 71.0 (dd, J = 28.3, 23.0 Hz), 46.9 (t, J = 5.9 Hz), 26.5, 23.1. 19F NMR (282 MHz, CDCl3) δ: −115.2 (dd, 1F, J = 282.2, 4.2 Hz), −116.6 (d, 1F, J = 283.2 Hz), −118.2 (d, 1F, J = 272.0 Hz), −129.3 (ddd, 1F, J = 272.0, 20.1, 4.2 Hz). HRMS (ESI): calcd for C13H15F4N2O2 (M + H) 307.1064; found 307.1068. 2,2,3,3-Tetrafluoro-4-(furan-2-yl)-4-hydroxy-1-(pyrrolidin-1-yl)butan-1-one (8j). Yield 123 mg (83%). Colorless oil. Rf 0.32 (hexane/ EtOAc, 1/1). 1H NMR (300 MHz, CDCl3) δ: 7.44 (br s, 1H), 6.50 (d, 1H, J = 3.2 Hz), 6.44−6.33 (m, 1H), 5.32 (d, 1H, JH−F = 19.4 Hz), 4.45 (s, 1H), 3.81−3.66 (m, 2H), 3.60 (t, 2H, J = 6.9 Hz), 2.10−1.78 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3) δ: 159.9 (t, J = 27.0 Hz), 148.5, 143.3, 115.3 (m), 111.7 (m), 110.6, 110.1, 67.1 (dd, J = 28.7, 23.5 Hz), 48.5. 47.3 (t, J = 6.3 Hz), 26.6, 23.2. 19F NMR (282 MHz, CDCl3) δ: −115.4 (dd, 1F, J = 281.8, 10.6 Hz), −117.3 (dd, 1F, J = 281.8, 9.9 Hz), −119.2 (dd, 1F, J = 272.3, 9.9 Hz), −128.4 (ddd, 1F, J = 272.3, 19.4, 10.6 Hz). HRMS (ESI): calcd for C12H14F4NO3 (M + H) 296.0904; found 296.0911. 2,2,3,3-Tetrafluoro-4-hydroxy-1-(pyrrolidin-1-yl)-4-(thiophen-2yl)butan-1-one (8k). Yield 126 mg (81%). Colorless oil. Rf 0.24 (hexane/EtOAc, 1/1). 1H NMR (300 MHz, CDCl3) δ: 7.39−7.34 (m, 1H), 7.19−7,14 (m, 1H), 7.03 (dd, 1H, J = 4.9, 3.7 Hz), 5.53 (d, 1H, JH−F = 20.6 Hz), 4.78 (s, 1H), 3.82−3.69 (m, 2H), 3.61 (t, 2H, J = 6.9 Hz), 2.08−1.83 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3) δ: 160.2 (t, J = 26.9 Hz), 137.3, 127.39 (d, J = 1.4 Hz), 126.7, 126.6, 115.2 (m), 111.8 (m), 69.0 (dd, J = 29.6, 22.8 Hz), 48.7, 47.5 (t, J = 6.0 Hz), 26.6, 23.3 (d, J = 7.5 Hz). 19F NMR (282 MHz, CDCl3) δ: −114.7 (dd, 1F, J = 278.8, 12.7 Hz), −116.8 (dd, 1F, J = 278.8, 11.7 Hz), −117.7 (dd, 1F, J = 270.9, 12.7 Hz), −130.8 (dddd, 1F, J = 20.6, 12.7, 11.7, 5.1 Hz). HRMS (ESI): calcd for C12H14F4NO2S (M + H) 312.0676; found 312.0681. (E)-2,2,3,3-Tetrafluoro-4-hydroxy-6-phenyl-1-(pyrrolidin-1-yl)hex5-en-1-one (8l). Yield 113 mg (68%). Yellow oil. Rf 0.35 (hexane/ EtOAc, 2/1). 1H NMR (300 MHz, CDCl3) δ: 7.49−7.25 (m, 5H), 6.85 (d, 1H, J = 15.9 Hz), 6.28 (dd, 1H, J = 15.9, 6.2 Hz), 4.95−4.74 (m, 1H), 4.24 (d, J = 5.3 Hz, 1H), 3.75 (t, 2H, J = 6.7 Hz), 3.60 (t, J = 7.0 Hz, 2H), 2.09−1.79 (m, 4H). 13C NMR (75 MHz, CDCl3) δ: 160.0 (t, J = 26.9 Hz), 136.2 (s), 135.0, 128.7, 128.3, 126.9, 121.9, 116.1 (m), 111.7 (m), 71.3 (dd, J = 27.6, 24.0 Hz), 48.5, 47.3 (t, J = 6.3 Hz), 26.5, 23.2. 19F NMR (282 MHz, CDCl3) δ: −115.3 (dd, 1F, J = 279.3, 8.3 Hz), −116.4 (d, 1F, J = 279.3 Hz), −119.6 (d, 1F, J = 272.5 Hz), −129.0 (ddd, 1F, J = 272.5, 18.2, 8.3 Hz). HRMS (ESI): calcd for C16H18F4NO2 (M + H) 332.1268; found 332.1264. 2,2,3,3-Tetrafluoro-4-hydroxy-6-phenyl-1-(pyrrolidin-1-yl)hexan1-one (8m). Yield 110 mg (66%). Colorless oil. Rf 0.35 (hexane/ EtOAc, 2/1). 1H NMR (300 MHz, CDCl3) δ: 7.38−7.16 (m, 5H), 4.10 (ddd, 1H, JH−F = 20.1 Hz, J = 8.8, 4.4 Hz), 3.82 (d, 1H, J = 5.1 Hz), 3.79−3.67 (m, 2H), 3.60 (t, 2H, J = 6.9 Hz), 3.08−2.89 (m, 1H), 2.84−2.59 (m, 1H), 2.14−1.81 (m, 4H). 13C NMR (75 MHz, CDCl3) δ: 160.3 (t, J = 26.9 Hz), 141.4, 128.7, 128.6, 126.2, 116.8 (dddd, J = 261.6, 258.2, 27.9, 26.3 Hz), 111.7 (tdd, J = 264.5, 34.2, 30.2 Hz), 69.3 (dd, J = 27.9, 23.4 Hz), 48.6, 47.4 (t, J = 6.7 Hz), 31.4, 30.5 (s, J = 21.9 Hz), 26.6 (t, J = 1.7 Hz), 23.2. 19F NMR (282 MHz, CDCl3) δ: −116.1 (dd, 1F, J = 275.7, 8.2 Hz), −117.2 (d, 1F, J = 275.7 Hz), −121.2 (d, 1F, J = 270.7 Hz), −132.1 (ddd, 1F, J = 270.7, 20.1, 8.2 Hz). HRMS (ESI): calcd for C16H19F4NNaO2 (M + Na) 356.1244; found 356.1248. 4-Cyclohexyl-2,2,3,3-tetrafluoro-4-hydroxy-1-(pyrrolidin-1-yl)butan-1-one (8n). Yield 123 mg (79%). Colorless crystals. Mp 76−77 °C. Rf 0.34 (hexane/EtOAc, 1/1). 1HNMR (300 MHz, CDCl3) δ: 3.99−3.80 (m, 1H), 3.80−3.65 (m, 2H), 3.55 (dd, J = 15.7, 6.5 Hz, 3H), 2.08−1.54 (m, 10H), 1.47−1.05 (m, 5H). 13C{1H} NMR (75 MHz, CDCl3) δ: 160.3 (t, J = 27.0 Hz), 117.5 (dddd, J = 264.0, 260.0, 28.5, 24.4 Hz), 111.6 (dddd, J = 267.8, 263.1, 34.5, 29.5 Hz), 72.9 (dd, J = 27.1, 21.4 Hz), 48.5, 47.3 (t, J = 6.1 Hz), 38.1, 30.2, 26.8 (d, J = 2.1 Hz), 26.6−26.5 (m), 26.6 (t, J = 2.0 Hz), 26.3, 26.1, 23.2. 19F NMR (282 MHz, CDCl3) δ: −116.3 (dd, 1F, J = 275.3, 9.6 Hz), −118.4 (dd, 9458

DOI: 10.1021/acs.joc.6b01739 J. Org. Chem. 2016, 81, 9455−9460

Note

The Journal of Organic Chemistry 1F, J = 275.3, 10.4 Hz), −119.7 (dd, 1F, J = 270.5, 10.4 Hz), −128.6 (ddd, 1F, J = 270.5, 22.3, 9.6 Hz). HRMS (ESI): calcd for C14H22F4NO2 (M + H) 312.1581; found 312.1586. 2,2,3,3-Tetrafluoro-4-hydroxy-5,5-dimethyl-1-(pyrrolidin-1-yl)hexan-1-one (8o). Yield 100 mg (70%). Colorless crystals. Mp 52−53 °C. Rf 0.30 (hexane/EtOAc, 1/1). 1HNMR (300 MHz, CDCl3) δ: 3.84−3.65 (m, 4H), 3.56 (t, 2H, J = 7.0 Hz), 2.04−1.79 (m, 4H), 1.06 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3) δ: 160.4 (t, J = 27.1 Hz), 118.8 (m), 111.6 (tdd, J = 265.9, 33.0, 29.4 Hz), 75.2 (dd, J = 26.8, 21.1 Hz), 48.4, 47.3 (t, J = 5.9 Hz), 35.4, 26.8 (m), 26.5 (t, J = 2.2 Hz), 23.2. 19F NMR (282 MHz, CDCl3) δ: −114.5 (d, 1F, J = 268.1 Hz), −117.2 (m, 2F), −129.4 (m, 1F). HRMS (ESI): calcd for C12H20F4NO2 (M + H) 286.1425; found 286.1423. (E)-2,3,4,4,5,5-Hexafluoro-1,6-di(pyrrolidin-1-yl)hex-2-ene-1,6dione (9). KF (87 mg, 1.5 mmol) was added to a mixture of silane 1b (271 mg, 1 mmol) and DMF (0.2 mL) at 0 °C, and the mixture was allowed to warm to room temperature over 15 min and was then stirred for an additional 3 h. The mixture was quenched with water (4 mL) and extracted with hexane (3 × 4 mL); the combined organic phases were filtered through Na2SO4 and concentrated under reduced pressure, and the crude product was subjected to flash chromatography on silica gel eluting with hexane/ethyl acetate, 2/1 (Rf 0.25, hexane/ethyl acetate, 2/1). Further purification was performed by preparative HPLC. Column (21 × 250 mm, 5 μm), flow rate 10 mL min−1, mobile phase: isocratic, ethyl acetate/hexane, 60% ethyl acetate; retention time 7.95 min. Yield 50 mg (28%). Colorless oil. 1H NMR (300 MHz, CDCl3) δ: 3.71 (t, 2H, J = 6.8 Hz), 3.64−3.49 (m, 6H), 2.07−1.82 (m, 8H). 13C{1H} NMR (75 MHz, CDCl3) δ: 157.4 (m), 156.7 (m), 146.7 (dd, J = 267.5, 47.5 Hz), 141.4 (m), 110.7 (m), 48.1, 47.1 (m), 46.8 (m), 46.3, 26.6, 26.00, 24.1, 23.3. 19F NMR (282 MHz, CDCl3) δ: −118.0 (m, 2F), −119.6 (dtd, 2F, J = 18.5, 12.2, 6.6 Hz), −148.5 (dtt, J = 137.3, 23.3, 6.6 Hz), −160.7 (dtt, J = 137.3, 12.2, 5.8 Hz). HRMS (ESI): calcd for C14H17F6N2O2 (M + H) 359.1189; found 359.1184. 4-(Dimethylamino)-2,2,3,3-tetrafluoro-4-phenyl-1-(pyrrolidin-1yl)butan-1-one (7b). MeOTf (94 mg, 0.58 mmol) was added to a solution of N-(phenylmethylene)methanamine (0.5 mmol, 1 equiv) in dichloromethane (mL) at 0 °C, and the mixture was stirred for 30 min. Dichloromethane was evaporated under vacuum, and the reaction vessel was filled with argon followed by the addition of DMSO (0.5 mL) and silane 1b (271 mg, 1 mmol). The mixture was cooled to −10 °C, and dry KF (58 mg, 1 mmol) was added. The reaction mixture was slowly warmed to room temperature over 15 min, and the solution was stirred for 45 min at room temperature. The mixture was filtered through a short silica gel pad and washed with small amount of ethyl acetate; the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel. Yield 95 mg (57%).Yellow crystals. Mp 72−73 °C. Rf 0.29 (hexane/EtOAc, 2/1). 1 H NMR (300 MHz, CDCl3) δ: 7.41−7.29 (m, 5H), 4.38 (dd, 1H, JH−F = 25.2 Hz, J = 8.6 Hz), 3.78−3.60 (m, 2H), 3.55 (t, 2H, J = 6.9 Hz), 2.20 (s, 6H), 2.03−1.78 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3) δ: 159.2 (t, J = 26.9 Hz), 131.0 (d, J = 2.1 Hz), 129.4, 128.5, 128.1, 118.7 (dddd, J = 262.7, 260.5, 27.5, 25.2 Hz), 111.4 (dddd, J = 261.6, 268.5, 32.1, 28.7 Hz), 67.9 (dd, J = 27.3, 18.4 Hz), 48.1, 46.9 (m), 42.6 (m), 26.8, 23.4. 19F NMR (282 MHz, CDCl3) δ: −110.7 (d, 1F, J = 267.8 Hz), −114.7 (dd, 1F, J = 273.5, 6.6 Hz), −117.39 (d, 1F, J = 273.5 Hz), −119.8 (ddd, 1F, J = 267.8, 25.2, 5.9 Hz). HRMS (ESI): calcd for C16H20F4N2NaO (M + Na) 355.1404; found 355.1406. 4-Methyl-N-(2,2,3,3-tetrafluoro-4-oxo-1-phenyl-4-[pyrrolidin-1yl)butyl]benzenesulfonamide (11). KF (58 mg, 1 mmol) was added to a mixture of N-tosylimine (130 mg, 0.5 mmol), silane 1b (203 mg, 0.75 mmol), and dimethylformamide (0.25 mL) at −10 °C. The reaction mixture was slowly warmed to room temperature over 15 min, and the solution was stirred for 45 min at room temperature. The mixture was treated with Bu4NF·3H2O (316 mg, 1 mmol) and stirred at room temperature for 10 min. The mixture was filtered through a short silica gel pad and washed with a small amount of ethyl acetate; the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel. Yield 151 mg (66%). Colorless

crystals. Mp 201−202 °C. Rf 0.19 (hexane/EtOAc, 1/1). 1H NMR (300 MHz, acetone-d6) δ: 7.62 (d, 1H, J = 10.6 Hz), 7.48 (d, 2H, J = 8.3 Hz), 7.34−7.07 (m, 7H), 5.61−5.45 (m, 1H), 3.71−3.60 (m, 2H), 2.73 (t, 2H, J = 6.6 Hz), 2.30 (s, 3H), 2.03−1.84 (m, 4H). 13C{1H} NMR (75 MHz, acetone-d6) δ: 158.8 (t, J = 26.3 Hz), 143.7, 139.4, 134.0, 129.9, 129.8, 129.2, 128.9, 127.7, 116.9 (m), 111.9 (m), 59.3 (ddd, J = 27.2, 21.4, 5.9 Hz), 48.7, 47.3 (t, J = 6.7 Hz), 27.0, 23.7, 21.3. 19 F NMR (282 MHz, acetone-d6) δ: −114.1 (d, 1F, J = 287.1 Hz), −115.2 (d, 1F, J = 287.1 Hz), −116.8 (d, 1F, J = 267.8 Hz), −121.3 (dd, 1F, J = 267.8, 17.9 Hz). HRMS (ESI): calcd for C21H23F4N2O3S (M + H) 459.1360; found 459.1367.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.6b01739. Copies of NMR spectra for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Ministry of Science (Project MD-3256-2015-3) and the Russian Foundation for Basic Research (Project 15-33-20133).

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REFERENCES

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